Scientists identify genes that control smooth muscle contraction in digestive system

The human body, and those of other mammals, contains a number of ring-shaped structures made of smooth muscle encircling openings in hollow organs such as the intestines and bladder called sphincters. Smooth muscle is involuntarily controlled, unlike the muscles we use to walk, for example, so that we don't need to consciously move digested food from stomach to small intestine.

Dysfunction in the sphincters, either structurally or functionally, can have severe consequences leading to diseases that impair the ability of the muscle to contract or relax. This can lead to achalasia, which makes it difficult to swallow; gastroesophageal reflux disease (GERD), which allows stomach acid to enter the esophagus or incontinence of the bowels.

"A healthy sphincter opens transiently but remains closed most of the time, maintaining a basal tone. This basal tone requires constant generation of force produced by the contraction of smooth muscle cells that make up the sphincters," said the author. "However, the genetics governing how the sphincter smooth muscle stays contracted for such long periods of time remains unknown."

Smooth muscle operates by generating force as the muscle motor protein myosin and actin filaments move past each other. This happens after a molecule called the myosin regulatory light chain (MLC) is turned on through a common molecular transformation called phosphorylation. How much phosphorylation takes place is controlled by the relative amounts of two enzymes; calcium dependent MLC kinase (MLCK), which promotes phosphorylation, and calcium independent MLC phosphatase (MLCP), which reverses phosphorylation. Through this process, contraction and relaxation of the muscle is achieved.

To understand the molecular mechanism responsible for the involuntary and continuous contraction of the sphincter muscle, researchers examined the internal anal sphincter that controls bowel continence in mice. They showed that genetic deletion of the MLCP enzyme in the smooth muscle had no effect on the basal tone of the mouse sphincter, but deletion of MLCK essentially abolishes the basal tone and mice become incontinent as a result.

Experiments showed that local calcium releases have no direct role in muscle tone. Instead, three types of ion channels act in concert to generate a rise in cytosolic calcium which eventually results in MLCK activation and muscle tone.

To test this hypothesis researchers generated a line of mice in which one of these channels could be turned off in smooth muscle only. "These mice were a powerful tool for establishing our hypothesis," said the author. "They helped us identify the Tmem16a (also called Ano1) gene as a critical component for basal tone formation and fecal continence. When we were able to turn off the TMEM16A channels in these mice, they lost the majority of the basal tone and became incontinent. "

Identifying the genes underlying sphincter basal tone is an important step towards understanding sphincter disorders and developing new treatments for them.